TY - JOUR
T1 - Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities
AU - van Drie, R W A
AU - van de Wouw, J
AU - Zandbergen, L M
AU - Dehairs, J
AU - Swinnen, J V
AU - Mulder, M T
AU - Verhaar, M C
AU - MaassenVanDenBrink, A
AU - Duncker, D J
AU - Sorop, O
AU - Merkus, D
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/10
Y1 - 2024/10
N2 - Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET
A+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg
-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H
2O
2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H
2O
2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET
A+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H
2O
2-mediated coronary vasodilation.
AB - Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET
A+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg
-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H
2O
2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H
2O
2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET
A+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H
2O
2-mediated coronary vasodilation.
KW - Coronary microcirculation
KW - Metabolic syndrome
KW - Myocardial perfusion
KW - Reactive oxygen species
KW - Swine
UR - http://www.scopus.com/inward/record.url?scp=85194416687&partnerID=8YFLogxK
U2 - 10.1007/s00395-024-01055-z
DO - 10.1007/s00395-024-01055-z
M3 - Article
C2 - 38796544
SN - 0300-8428
VL - 119
SP - 869
EP - 887
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 5
ER -